The present invention relates to substituted 2-pyridine cyclohexane-1,4-diamine compounds, to a process for their production, pharmaceutical compositions containing these compounds and to therapeutic uses of substituted 2-pyridine cyclohexane-1,4-diamine compounds.
The heptadecapeptide nociceptin is an endogenous ligand of the ORL1 (opioid receptor-like) receptor (Meunier et al., Nature 377, 1995, p. 532–535), which belongs to the family of opioid receptors and can be found in many regions of the brain and spinal cord (Mollereau et al., FEBS Letters, 341, 1994, p. 33–38, Darland et al., Trends in Neurosciences, 21, 1998, p. 215–221). The peptide is characterised by a high affinity, with a Kd value of approximately 56 pM (Ardati et al., Mol. Pharmacol. 51, p. 816–824), and by a high selectivity for the ORL1 receptor. The ORL1 receptor is homologous to the μ, κ and δ opioid receptors and the amino acid sequence of the nociceptin peptide displays a strong similarity to those of the known opioid peptides. The nociceptin-induced activation of the receptor, via coupling with Gi/o proteins, leads to an inhibition of adenylate cyclase (Meunier et al., Nature 377, 1995, p. 532–535). On a cellular level too there are functional similarities between the μ, κ and δ opioid receptors and the ORL1 receptor with regard to the activation of the potassium channel (Matthes et al., Mol. Pharmacol. 50, 1996, p. 447–450; Vaughan et al., Br. J. Pharmacol. 117, 1996, p. 1609–1611) and the inhibition of the L, N and P/Q type calcium channels (Conner et al., Br. J. Pharmacol. 118, 1996, p. 205–207; Knoflach et al., J. Neuroscience 16, 1996, p. 6657–6664).
After intracerebroventicular administration the nociceptin peptide displays a pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al., Science 270, 1995, p. 792–794; Hara et al., Br. J. Pharmacol. 121, 1997, p. 401–408). These findings can be explained as inhibition of stress-induced analgesia (Mogil et al., Neurosci. Letters 214, 1996, p. 131–134; and Neuroscience 75, 1996, p. 333–337). In this connection an anxiolytic activity of nociceptin has also been demonstrated (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854–14858).
On the other hand, an antinociceptive effect of nociceptin has also been demonstrated in various animal models, particularly after intrathecal administration. Nociceptin inhibits the activity of kainate- or glutamate-stimulated basal ganglia neurones (Shu et al., Neuropeptides, 32, 1998, 567–571) or glutamate-stimulated spinal cord neurones (Faber et al., Br. J. Pharmacol., 119, 1996, p. 189–190); it has an antinociceptive action in the tail flick test in mice (King et al., Neurosci. Lett., 223, 1997, 113–116), in the flexor reflex model in rats (Xu et al., NeuroReport, 7, 1996, 2092–2094) and in the formalin test in rats (Yamamoto et al., Neuroscience, 81, 1997, p. 249–254). An antinociceptive action of nociceptin has also been demonstrated in models for neuropathic pain (Yamamoto and Nozaki-Taguchi, Anesthesiology, 87, 1997), which is particularly interesting in as much as the activity of nociceptin increases after axotomy of the spinal nerves. This is in contrast to the classical opioids, whose activity decreases under these conditions (Abdulla and Smith, J. Neurosci., 18, 1998, p. 9685–9694).
Furthermore, the ORL1 receptor is also involved in the regulation of other physiological and pathophysiological processes. These include among others learning and memory development (Sandin et al., Eur. J. Neurosci., 9, 1997, p. 194–197; Manabe et al., Nature, 394, 1997, p. 577–581), hearing (Nishi et al., EMBO J., 16, 1997, p. 1858–1864), eating (Pomonis et al., NeuroReport, 8, 1996, p. 369–371), blood pressure regulation (Gumusel et al., Life Sci., 60, 1997, p. 141–145; Campion and Kadowitz, Biochem. Biophys. Res. Comm., 234, 1997, p. 309–312), epilepsy (Gutiérrez et al., Abstract 536.18, Society for Neuroscience, Vol. 24, 28th Ann. Meeting, Los Angeles, Nov. 7–12, 1998) and diuresis (Kapista et al., Life Sciences, 60, 1997, PL 15–21). An overview article by Calo et al. (Br. J. Pharmacol., 129, 2000, 1261–1283) gives an overview of the indications or biological processes in which the ORL1 receptor plays or with a high degree of probability could play a part. Those cited include: analgesia, stimulation and regulation of eating, influence on μ-agonists such as morphine, treatment of withdrawal symptoms, reduction of the addiction potential of morphines, anxiolysis, modulation of motor activity, amnesia, epilepsy; modulation of neurotransmitter release, particularly of glutamate, serotonin and dopamine, and hence neurodegenerative diseases; influencing of the cardiovascular system, triggering of an erection, diuresis, antinatriuresis, ionic equilibrium, aterial blood pressure, water-storage disorders, intestinal motility (diarrhoea), relaxing effects on the respiratory tracts, micturation reflex (urinary incontinence). The use of agonists and antagonists as anoretics, analgesics (also in coadministration with opioids) or nootropics is also discussed.
The possible applications of compounds that bind to the ORL1 receptor and activate or inhibit it are correspondingly diverse.